1. Field of the Invention
The present invention relates to cyclooxygenase inhibitors, and particularly to 2-(5-methoxy-2-methyl-1-indol-3yl)-N-[(E)-substituted phenyl methylidine] aceto hydrazide derivatives.
2. Description of the Related Art
Conversion of arachidonic acid to prostaglandin H2 (PGH2) is catalyzed by the cyclooxygenase (COX) enzyme. Because the prostaglandin H2 is an unstable intermediate, it is converted to many prostanoids by specific isomerase enzymes. This process of biosynthesis occurs in all tissues of the human body. Pain and fever associated with inflammation are the non-beneficial effects of prostaglandins, while gastro-intestinal protection and platelet function are among their beneficial effects. The COX enzyme has two isoforms, COX-1 and COX-2, which are each regulated differently. COX-1 provides cytoprotection in the gastrointestinal (GI) tract and COX-2 mediates inflammation.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective analgesics frequently used in palliative care. However, these medicines are related with numerous adverse side effects that are largely due to gastrointestinal toxicity, with subsequent complications, such as gastroduodenal perforations, ulcers and bleeds. Such toxicity is typically ascribed to the inhibition of cyclooxygenase-1 (COX-1). Thus, selective inhibitors of cyclooxygenase-2 (COX-2) were developed in an attempt to reduce these side effects. Trial studies to date confirm that these drugs do indeed have a reduced incidence of gastro-duodenal toxicity. Prior to the introduction of the COX-2 selective inhibitors, patients at high risk were often prescribed a gastro-protective agent (such as misoprostol or a proton pump inhibitor) with a conventional NSAID.
Most of the common nonsteroidal anti-inflammatory drugs (NSAIDs) show a greater selectivity for COX-1 than COX-2. Thus, long term use of NSAIDS may produce gastric irritation, bleeding and ulceration. It is assumed that inhibition of COX-2 selectively would result in the same anti-inflammatory benefits that non-selective NSAIDs provide but with fewer incidences of gastrointestinal side effects. COX-2 inhibitors provide synthesis of cytoprotection prostaglandins, reducing ulceration and bleeding, however COX-2 inhibitors have also been found to have cardiovascular side effects.
Indomethacin is an indole acetic acid derivative NSAID known to induce ulceration. Chemical modifications have improved the safety profile of various NSAIDs, thus showing the possibility for synthetic modifications to result in an increased anti-inflammatory activity with reduced ulcerogenicity. It would be desirable to provide an indole derivative having the anti-inflammatory and analgesic properties of a COX-2 inhibitor NSAID, but which also provides gastric sparing activity.
Thus, a COX-2 inhibitor solving the aforementioned problems are desired.